Abstract

Background

Reovirus serotype 3 (REO) is a Dearing strain, non-enveloped virus with limited pathogenicity in humans. REO is an oncolytic virus that specifically targets cells with activated Ras signalling and gemcitabine (GEM) has shown efficacy in a wide range of tumours commonly driven by activated Ras signalling. Moreover, multiple pre-clinical experiments suggest that REO is able to synergize with GEM.

Method

This open-label, dose-escalating phase-I trial studied the combination of intravenous (iv) REO, starting at 3x109 TCID50 d1-5 and iv GEM, 1000mg/m2 d1 and 8 in a 3 week cycle. We planned to dose escalate Reo. Primary endpoints were: MTD, DLT, safety profile of REO/GEM and to establish a recommended phase 2 dose (RP2D).

Results

16 heavily pre-treated patients entered this trial. The first 2 patients on study both had a DLT (patient 1: transaminase increase; patient 2: Troponin-I increase) probably related to both drugs. The dose of REO was adjusted to 1x109 TCID50, d1 of each cycle and increased in subsequent cohorts to 3x109, 1x1010, and 3x1010 TCID50, d1. In total 47 cycles were administered resulting in multiple expected toxicities including fever, headaches, rhinorrhea, fatigue and myelosupression. In the cohort with 3x1010 TCID50 we observed 1 DLT in a 3 patient cohort, being a transient grade 3 transaminase rise probably related to REO. Of the 11 pts evaluable for response, 2 pts had PR and/or clinical response and 5 pts had SD for up to 4-8 cycles, amounting for a total disease control rate (CR+PR+SD) of 64%.

Conclusion

REO and GEM could not be combined at full dose but after dose reduction of the REO the combination is well-tolerated and results in disease control for 64% of patients. We did not establish an MTD but REO 1x1010 TCID50 d1 combined with GEM would be acceptable as RP2D.